Considerations for Setting the Specifications of Vaccines

Abstract and Introduction

Abstract

The specifications of vaccines are determined by the particular product and its method of manufacture, which raise issues unique to the vaccine in question. However, the general principles are shared, including the need to have sufficient active material to immunize a very high proportion of recipients, an acceptable level of safety, which may require specific testing or may come from the production process, and an acceptable low level of contamination with unwanted materials, which may include infectious agents or materials used in production. These principles apply to the earliest smallpox vaccines and the most recent recombinant vaccines, such as those against HPV. Manufacturing development includes more precise definitions of the product through improved tests and tighter control of the process parameters. Good manufacturing practice plays a major role, which is likely to increase in importance in assuring product quality almost independent of end-product specifications.

Introduction

Medicines, including vaccines, are judged by the three factors of safety, efficacy and quality. Safety and efficacy can only be demonstrated by the use of the medicine in the target population in clinical trials or general use. They relate to the number and type of adverse events that are recorded and the extent to which the medicine has the desired effect; while there are indications from nonclinical and preclinical tests, only clinical usage can provide a real evaluation.

However, experience with one batch provides no assurance of the performance of the next unless the product is made in a consistent way and complies with relevant test specifications, demonstrating that it contains the correct active ingredient and is free of contaminants. The precise tests and the specifications vary widely according to the vaccine involved, including its mode of production so that general specifications are largely meaningless. However, general principles concerning potency, safety and possible contamination can be derived and are the subject of this review. Table 1 summarizes some of the specific considerations for the four vaccines considered below. It is intended to be illustrative rather than comprehensive and other specifications including those for process residuals and excipients will be applicable to medicines in general, not just vaccines. For vaccines, however, the use of adjuvants may be a specific additional factor; for many years only aluminum salts were acceptable but more complex manufacturer-specific mixtures are now in use, and may require correspondingly complex specifications to ensure consistency. Discussion is restricted to vaccines that are or have been widely used in immunization programs, and does not cover early or experimental stage vaccines although the same principles apply.

Table 1. Summary specifications of four viral vaccines.
Vaccine	Potency	Safety	Contamination
Smallpox (live vaccinia)	108 pock-forming units per ml	No smallpox virus-specific tests	Various specific adventitious agents. Bacterial load
Live oral polio vaccine		Monkey neurovirulence, mouse neurovirulence, mutant analysis by molecular means (MAPREC)	General adventitious agents plus specific agents for vaccine made in primary monkey kidney cells (SV40, SCMV and B virus)
Influenza (inactivated)	15 µg HA as measured by assay of functional protein (e.g., by SRD)	Egg isolates used as seeds. Passage of seed virus restricted	Egg protein, endotoxin. No adventitious agent testing
Recombinant HPV-like particle	ELISA units set by manufacturer using conformation-dependent monoclonal antibodies	No papilloma-specific tests	Purity and integrity of L1 protein. Insect viruses, cellular DNA for insect cell grown vaccines

HA: Hemagglutinin antigen; MAPREC: Mutant analysis by PCR and restriction enzyme cleavage; SCMV: Simian cytomegalovirus; SRD: Single radial immunodiffusion; SV40: Simian virus 40.

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